Can we predict sub-optimal treatment response?


Short-term suboptimal response criteria for predicting long-term non-response to first-line disease modifying therapies in multiple sclerosis: A systematic review and meta-analysis

Jordi Ríoa, Juan Luís Ruiz-Peña doi:10.1016/j.jns.2015.12.043



There is no consensus about short-term suboptimal response to first-line treatments in relapsing-remitting multiple sclerosis.


We searched studies with interferon beta or glatiramer acetate in which a long-term (≥ 2 years (y)) outcome could be predicted using short-term (≤ 1 y) suboptimal response criteria (EDSS-, imaging- and/or relapse-based). We obtained pooled diagnostic accuracy parameters for the 1-y criteria used to predict disability progression between 2–5 y.


We selected 45 articles. Eight studies allowed calculating pooled estimates of 16 criteria. The three criteria with best accuracy were: new or enlarging T2-weighted lesions (newT2) ≥ 1 (pooled sensitivity: 85.5%; specificity:70.2%; positive predictive value:48.0%; negative predictive value:93.8%), newT2 ≥ 2 (62.4%, 83.6%, 55.0% and 87.3%, respectively) and RIO score ≥ 2 (55.8%, 84.4%, 47.8% and 88.2%). Pooled percentages of suboptimal responders were 43.3%, 27.6% and 23.7%, respectively. Pooled diagnostic odds ratios were 14.6 (95% confidence interval: 1.4–155), 9.2 (1.4–59.0) and 8.2 (3.5–19.2). 


All criteria had a limited predictive value. RIO score ≥ 2 at 1-y combined fair accuracy and consistency, limiting the probability of disability progression in the next years to 1 in 8 optimal responders. NewT2 ≥ 1 at 1-y had similar positive predictive value, but diminished the false negatives to 1 in 16 patients. More sensitive measures of treatment failure at short term are needed.

Table: Rio and modified Rio scores.

Rio score
MRI criterion = 1 if the patient had (on the yearly MRI scan) > 2 active T2 lesions, defined as new or enlarging T2-weighted lesions, plus the number of gadolinium-enhancing (Gd) T1-weighted lesions over the first year

Relapse criterion = 1
if the patient experienced ≥ 1 relapse over the first year

EDSS criterion = 1

if there was an increase in the patient’s EDSS score of ≥1 point, sustained over at least 6 months and confirmed at the end of the follow-up period.

The sum of these three criteria classifies patients into those having a score of 0, 1, 2 or 3
Modified Rio score
MRI criterion = 1 if the patient has had > 4 new T2 lesions
Relapse criterion = 1 if the patient experienced 1 relapse
Relapse criterion = 2 if the patient experienced ≥ 2 relapses

Score = 0

if new T2 lesions ≤ 4 and relapses = 0
Score = 1 if new T2 lesions ≤ 4 and relapses = 1; or new T2 lesions >4 and relapses = 0
Score = 2 if new T2 lesions ≤ 4 and relapses ≥ 2; or new T2 lesions >4 and relapses = 1
Score = 3 if new T2 lesions > 4 and relapses ≥ 2

Figure: Sensitivity for predicting long-term non-response with the proportion of non-responders at long term that are classified as suboptimal responders at short term.

Owing to the heterogeneous nature of MS presentations it is difficult to predict the prognosis of MS at an individual level. As we for aim for NEDA (no evidence of disease activity) in practice, we need to find ways of fine tuning the ways in which we go about doing this. In this case defining at an individual level the sub-optimal responders to treatment in the short-term (i.e. <1 year). This would allow for early escalation of treatment before there is irreversible neurological injury.

The commonly proposed measures are relapses, EDSS progression, MRI activity or a combination of all three. The Rio score (and also the modified Rio score) are based on disability progression, relapses and MRI (see Table above). According to the scores, you can either be in the low-risk category (score 0 or 1), or high-risk category (score 2 or 3) for suboptimal treatment response. This is not fool-proof method and overall they demonstrate little predictive value of picking out long-term non-responders within the first year of treatment. And this is what the authors found in this study. Moreover, according to the authors around 1 in 2 of suboptimal responders will not go on to develop disability progression based on these criteria!

However, they found that the most predictive measures were those based only on MRI, or on clinical and MRI measures. In general, those based on clinical measures (EDSS  ≥ 1; the most commonly used criterion of long-term non-response) had a lower diagnostic accuracy. New or enlarging T2 lesions (new T2 ≥ 1) had higher diagnostic accuracy than Gd enhancing lesions (see Figure above).

So T2 lesions are the best we have, but do we know anything about the timing of new T2 lesions appear and the beginning of the treatment effect? From a practical point this doesn’t matter, but will make clinicians reliant on yearly MRI’s. Definitely more sensitive measures of disease course and treatment failure are therefore needed.

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Neuro Doc Gnanapavan




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